Polymeric devices that steadily release controlled amounts of therapeutic agents are useful to overcome variations in blood levels of these agents that often occur with administration, either orally or by injection. Such devices, including implants, transdermal and parenteral drug delivery materials, and polymeric microspheres have been found to be extremely useful for this purpose. Rembaum et al, U.S. Pat. No. 4,138,383; Yen et al, U.S. Pat. No. 4,157,323; Poste et al, Biotechnology, (December 1983), pp. 869-877.
The use of microsphere drug delivery systems enables a therapeutic agent to be released in a specified area or over a specified time period. The polymer which constitutes the microsphere particle must be able to form a stable attachment with the therapeutic agent through covalent bonding or physical adsorption or entrapment to avoid premature release in the host organism, but the attachment must also be reversible to enable release of the therapeutic agent at the appropriate site.
The size of the particles is an important parameter which governs the efficacy of the drug delivery system. Microsphere particles which are especially useful are nanoparticles which are small colloidal particles of less than about 1 micrometer in diameter. Couvreur et al, in Polymeric Nanoparticles and Microspheres, Guiot, P. and Couvreur, P., ed., CRC Press, Boca Raton, Fla., pp. 27-93.
It is advantageous to incorporate active therapeutic agents, e.g., drugs, into carrier polymer particles, or microspheres, for administration into the blood stream of a host mammal rather than inject the agents themselves. This is to facilitate drug solubilization, avoid rapid degradation, and toxicity, and to control blood levels of the agent. However, after intravenous injection, most types of microspheres tend to be cleared rapidly from the blood by macrophages of the reticulo-endothelial system (RES).
This difficulty is due to the adsorption of certain blood proteins onto the surfaces of the microspheres. The presence of these adsorbed proteins results in the uptake of the particles by macrophages and their rapid clearance from blood by the RES. Since the major part of this process occurs within the lever, microspheres can easily be targeted to the Kupffer cells of the liver, and to a lesser extent to spleen and bone marrow. Such "passive targeting is advantageous when the objective is imaging these organs in a diagnostic method or trying to achieve the slow release of carrier-entrapped drugs after uptake into macrophages within these organs. However, it sequestration at other sites is required, when it is necessary to prevent the normal RES clearance.
To deliver drugs, for example, to a tumor outside the RES, it is necessary to avoid RES clearance of the drug and carrier in order to achieve prolonged circulation in the blood. Additionally, it is necessary to be able to pass across the microvasculature to the tissue/organ site in order to have adequate sequestration in the target tissue. RES clearance can be suppressed either with RES-blockading agents, or by controlling the surface characteristics of particles to make them less susceptible to serum protein mediated RES clearance.
If particles, however, acquire a coating of serum factors (serum proteins), accelerated RES-mediated clearance occurs. Protein adsorption on film surfaces can be reduced by the attachment of polyethylene oxide chains to the polymer material. Andrade et al, Adv. Poly. Sci. 79: 1-63 (1986); Nagaoka et a, in Polymers as Biomaterials (Shalaby et al, eds.) Plenum Press, pp. 361-374 (1984); U.S. Pat. No. 4,424,311.
Polyethylene oxide (PEO) has been found to be an effective polymer to attach to a film surface for producing low protein adsorption and low cell adhesion characteristics, due to its high mobility, unique solution properties, molecular conformation in aqueous solution and steric stabilization effects. PEO-water interfaces have very low interfacial free energies, and thus low driving forces for adsorption.